Recent advance in neuroscience are making clear the natural shape of neurotransmitter, substance deeply related to memory in the brain. It is said that some of these substances are neuropeptides containing prolines.
Recovery of the memory was reported by the dosing neuropeptide containing proline to experimental amnesia rats (See Science 211, 601 (1981)).
On the other hand, it is presumed that these neuropeptide-hormones shall be metabolized by cerebral endogenous peptidases. Especially, prolyl endopeptidase (EC, 3. 4. 21. 26) might take part in these metabolisms closely (See J. Biochem., 94, 1179 (1983)).
From these facts, the studies were in progress that it should be possible to prevent or treat amnesia by inhibiting prolyl endopeptidase and suppressing the metabolism of neurotransmitters. (See Protein, Nucleic acid and Enzyme 25(6), 513(1980); Nippon Nougei Kagaku Kaishi 58(11), 1147(1984); J. Neurochem., 41, 69(1983); ibid 42, 237(1984).)
For the purpose described above, several compounds were synthesized. For example, it is clear that N-benzyloxycarbonyl-glycyl-L-prolyl-chloromethane, N-benzyloxycarbonyl-L-prolyl-prolinal strongly inhibit prolyl endopeptidase (See J. Neurochem., 41, 69 (1983)). More recently, it is disclosed that the compounds shown below are effective for the above purpose.
(i) Pyrrolidine derivatives of the general formula: ##STR3## wherein, R.sup.1 represents ##STR4## R.sup.2 represents lower alkyl group, phenyl group which is unsubstituted or substituted or --CH.sub.2 --R.sup.22. With the proviso that R.sup.3, R.sup.4, R.sup.5 independently represent hydrogen atom, halogen atom, hydroxy group, lower alkyl group, phenyl group which is unsubstituted or substituted, --CH.sub.2 R.sup.9, --X--R.sup.10, --O--CO--R.sup.12, --NH.sub.2, --NHR.sup.14 or NR.sup.17 R.sup.18, with the proviso that R.sup.9 represents phenyl group which is unsubstituted or substituted. X represents an oxygen atom or sulfur atom. R.sup.10 represents an lower alkyl group, phenyl group which is substituted or unsubstituted or --CH.sub.2 R.sup.11, with the proviso that R.sup.11 represents phenyl group which is unsubstituted or substituted. R.sup.12 represents lower alkyl group, phenyl group which is unsubstituted or substituted or --CH.sub.2 R.sup.13, with the proviso that R.sup.13 represents phenyl group which is unsubstituted or substituted. R.sup.15 represents lower alkyl group, cycloalkyl group of 5 or 6 ring members, phenyl group which is unsubstituted or substituted, --CH.sub.2 R.sup.15, with the proviso that R.sup.15 represents phenyl group unsubstituted or substituted or --CO--R.sup.16, with the proviso that R.sup.16 represents lower alkyl group or phenyl group which is unsubstituted or substituted. R.sup.17 and R.sup.18 independently represent lower alkyl group or --CH.sub.2 R.sup.19, with the proviso that R.sup.19 represents phenyl group which is unsubstituted or substituted. R.sup.6 represents a hydrogen atom or lower alkyl group. R.sup.7 represents a hydrogen atom, lower alkyl group, benzyl group, CH.sub.3 --CH(OH)-- or --(CH.sub.2).sub.n --R.sup.20 with the proviso that n represents an integer of from 0 to 4. R.sup.20 represents --OH, --SH, --NH.sub.2, --SCH.sub.3, ##STR5## --CONH.sub.2, --NH--C(.dbd.NH)--NH.sub.2, CO.sub.2 R.sup.21, with the proviso that R.sup.21 represents hydrogen atom, lower alkyl group or benzyl group, or heterocyclic ring group. R.sup.8 represents hydrogen atom or 5-membered heterocyclic ring group together with R.sup.7 and nitrogen atom, and carbon atom which are neighboured. R.sup.22 represents phenyl group which is unsubstituted or substituted. See Japanese Patent Kokai No. 62-221666, i.e., European Patent Publication No. 238319.
ii) Pyrrolidine derivatives of its general formula: ##STR6## wherein, R.sup.1 represents ##STR7## R.sup.2 represents ##STR8## with the proviso that, R.sup.3, R.sup.4 and R.sup.5 independently represent hydrogen atom, halogen atom, hydroxy group, lower alkyl group, phenyl group which is unsubstituted or substituted, --CH.sub.2 R.sup.9, --X--R.sup.10, --O--CO--R.sup.12, --NH.sub.2, --NHR.sup.14 or --NR.sup.17 R.sup.18, with the proviso that R.sup.9 represents phenyl group which is unsubstituted or substituted. X represents an oxygen atom or sulfur atom. R.sup.10 represents lower alkyl group, phenyl group which is unsubstituted or substituted, or --CH.sub.2 R.sup.11, with the proviso that R.sup.11 represents phenyl group which is unsubstituted or substituted. R.sup.12 represents lower alkyl group, phenyl group which is unsubstituted or substituted or --CH.sub.2 R.sup.13, with the proviso that R.sup.13 represents phenyl group which is unsubstituted or substituted. R.sup.14 represents lower alkyl group, cycloalkyl group of 5 or 6 rings members, phenyl group which is unsubstituted or substituted, --CH.sub.2 R.sup.15, with the proviso that R.sup.15 represents phenyl group which is unsubstituted or substituted, or --COR--R.sup.16, with the proviso that R.sup.16 represents lower alkyl group, or phenyl group which is unsubstituted or substituted. R.sup.17 and R.sup.18 independently represent lower alkyl group or --CH.sub.2 R.sup.19, with the proviso that R.sup.19 represents phenyl group which is unsubstituted or substituted. R.sup.6 represents hydrogen atom or lower alkyl group. R.sup.7 represents hydrogen atom, lower alkyl group, benzyl group, CH.sub.3 --CH(OH)-- or --(CH.sub.2).sub.n --R.sup.20 with the proviso that n represents an integer of from 0 to 4. R.sup.20 represents --OH, --SH, --NH.sub.2, --SCH.sub.3, ##STR9## --CONH.sub.2, --NH--C(.dbd.NH)--NH.sub.2, --CO.sub.2 R.sup.21, with the proviso that, R.sup.21 represents hydrogen atom, lower alkyl group or benzyl group, or heterocyclic ring group. R.sup.8 represents hydrogen atom, or 5-membered heterocyclic ring group together with R.sup.7 and a nitrogen atom and carbon atom which are neighboured. R.sup.22 presents hydrogen atom, lower alkyl group, phenyl group which is unsubstituted or substituted, or --CH.sub.2 R.sup.24, with the proviso that R.sup.24 represents phenyl group which is unsubstituted or substituted. R.sup.23 represents lower alkyl group or when R.sup.25 and R.sup.23 are each taken together, they represent lower alkylene group. See Japanese Patent Kokai No. 62-221667, i.e., European Patent Publication No. 238319.
The present inventors have also filed an application related to prolinal derivatives having an activity of anti-amnesia, in advance of the present application, i.e.:
(iii) Prolinal derivatives of general formula: ##STR10## wherein A represents alkylene or alkenylene group of from 1 to 8 carbon atom(s) or a saturated hydrocarbon ring of from 3 to 7 carbon atoms, R represents hydrogen atom, phenyl group, benzyl group, alkyl group of from 1 to 8 carbon atom(s) or cycloalkyl group of from 3 to 7 carbon atoms, B represents alkylene group of from 1 to 8 atom(s) unsubstituted or substituted by phenyl group or benzyl group or a single bond, D represents carbocyclic or heterocyclic ring unsubstituted or substituted by from one to three of halogen atom, alkyl or alkoxy group of from 1 to 4 carbon atom(s), nitro group or trifluoromethyl group. See Japanese Patent Application No. 62-290631, i.e., European Patent Publication No. 268190.